Abstract
In these studies, we explored for the first time the molecular relationship between the paired-domain-containing transcription factor, Pax9, and the ectodysplasin (Eda) signaling pathway during mouse incisor formation. Mice that were deficient in both Pax9 and Eda were generated, and the status of dentition analyzed in all progeny using gross evaluation and histomorphometric means. When compared to wildtype controls, Pax9+/–Eda–/– mice lack mandibular incisors. Interestingly, Fgf and Shh signaling are down-regulated while Bmp4 and Lef1 appear unaffected. These findings suggest that Pax9-dependent signaling involves the Eda pathway and that this genetic relationship is important for mandibular incisor development. Studies of records of humans affected by mutations in PAX9 lead to the congenital absence of posterior dentition but interestingly involve agenesis of mandibular central incisors. The latter phenotype is exhibited by individuals with EDA or EDAR mutations. Thus, it is likely that PAX9, in addition to playing a role in the formation of more complex dentition, is also involved with EDA signaling in the initiation of odontogenesis within the incisal domain.
Highlights
The formation of mammalian dentition is a remarkable developmental process and a valuable model for studying epithelial–mesenchymal signaling interactions that control patterning morphogenesis
Through the use of mouse genetics, we demonstrate that Pax9-dependent signaling is functionally integrated with Eda signaling during mandibular incisor development
The compound mutant Pax9+/−Eda−/− mice exhibited missing third molars in both the mandible and maxilla, as well as missing mandibular incisors (Figures 1C,F,G). These data suggest that Pax9 and Eda-dependent signaling pathway genes share a genetic interaction in controlling the molar number and the formation of mandibular incisors
Summary
The formation of mammalian dentition is a remarkable developmental process and a valuable model for studying epithelial–mesenchymal signaling interactions that control patterning morphogenesis. Classified as genetically and phenotypically heterogeneous, tooth agenesis most commonly affects third molars, mandibular second premolars, maxillary lateral incisors, and maxillary second premolars (Kapadia et al, 2007; Nieminen, 2009; Ye and Attaie, 2016; Williams and Letra, 2018). These commonly missing teeth represent the most distal members of each tooth family and fail to develop due to a disruption in normal signaling. This suggests that distinct distal-proximal morphogenetic gradients are involved in guiding the patterning of human dentition
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